PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer.
PI3K/Akt/mTOR Signaling and Plasma Membrane Proteins Are Implicated in Responsiveness to Adjuvant Dendritic Cell Vaccination for Metastatic Colorectal Cancer.
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DOI：
10.1158/1078-0432.ccr-16-0623
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发表时间：
2017-01-15
期刊：
影响因子：
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通讯作者：
Barth RJ Jr
中科院分区：
文献类型：
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作者：
Qian DC;Xiao X;Byun J;Suriawinata AA;Her SC;Amos CI;Barth RJ Jr
我们先前已经证明，与未发生免疫应答的患者相比，对树突状细胞（DC）疫苗表现出免疫应答的转移性结直肠癌患者在手术后具有上级的无复发生存率。我们试图描述T淋巴细胞浸润和转移瘤体细胞突变的模式，这些模式与DC疫苗相关并可预测DC疫苗的应答。在疫苗接种前，通过免疫组织化学对22例患者（11例应答者和11例无应答者）切除的转移灶和周围正常肝组织中的细胞毒性、记忆和调节性T细胞进行计数。结合肿瘤测序，使用组合多变量和折叠方法来鉴定与疫苗应答相关的基因突变。我们还使用他/她的肿瘤基因型数据和从其他21例患者计算的变异相关效应大小推导出每例患者的缓解预测评分;对具有细胞膜相关功能的基因产物给予更大的权重。疫苗应答与肿瘤内、肿瘤周围或肝脏T细胞亚群密度之间无相关性。相关基因在PI 3 K/Akt/mTOR信号转导轴中富集（P < 0.001）。在22轮留一交叉验证中应用一致的预测评分截止值，在22名患者中的21名（95%）中正确推断疫苗应答。佐剂树突状细胞疫苗接种已显示出作为转移性结直肠癌患者免疫治疗的一种形式的前景。其疗效可能受到影响PI 3 K、Akt和mTOR通路以及肿瘤表面蛋白的体细胞突变的影响。
We have previously demonstrated that metastatic colorectal cancer patients who exhibit immune responses to a dendritic cell (DC) vaccine have superior recurrence-free survival following surgery, compared to patients in whom responses do not occur. We sought to characterize the patterns of T lymphocyte infiltration and somatic mutations in metastases that are associated with and predictive of response to the DC vaccine. Cytotoxic, memory, and regulatory T cells in resected metastases and surrounding normal liver tissue from 22 patients (11 responders and 11 non-responders) were enumerated by immunohistochemistry prior to vaccine administration. In conjunction with tumor sequencing, the Combined Multivariate and Collapsing method was used to identify gene mutations that are associated with vaccine response. We also derived a response prediction score for each patient using his/her tumor genotype data and variant association effect sizes computed from the other 21 patients; greater weighting was placed on gene products with cell membrane-related functions. There was no correlation between vaccine response and intra-tumor, peri-tumor, or hepatic densities of T cell subpopulations. Associated genes were found to be enriched in the PI3K/Akt/mTOR signaling axis (P < 0.001). Applying a consistent prediction score cutoff over 22 rounds of leave-one-out cross-validation correctly inferred vaccine response in 21 of 22 patients (95%). Adjuvant dendritic cell vaccination has shown promise as a form of immunotherapy for patients with metastatic colorectal cancer. Its efficacy may be influenced by somatic mutations that affect pathways involving PI3K, Akt, and mTOR, as well as tumor surface proteins.